Despite advances in therapy, HIV-infected individuals remain at higher risk for kidney dysfunction than uninfected individuals. Current measures of kidney function, such as serum creatinine and dipstick proteinuria, are late and nonspecific markers of kidney damage in HIV-infected individuals, and do not differentiate the etiology or site of injury within the nephron. Early identification of tubular dysfunction is particularly important in HIV-infected persons receiving tenofovir, an antiretroviral medication with direct toxicity to proximal tubular epithelial cells. We propose a novel paradigm for the assessment of kidney health in HIV-infected individuals, using a panel of urinary biomarkers which can detect early kidney injury, localize pathology within the nephron, and differentiate drug toxicity from alternate etiologies of kidney damage. We recently measured urine levels of interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), a1-microglobulin (a1m), and albuminuria in 886 HIV-infected and 350 uninfected men enrolled in the Multicenter AIDS Cohort Study (MACS). The current project will compare levels of each biomarker between HIV-infected and uninfected men; identify the specific risk factors associated with each biomarker among the HIV-infected participants; determine the impact of tenofovir use on kidney health based on biomarker levels; and evaluate longitudinal associations of each urine biomarker with kidney function decline over 4 years. Identification of early kidney injury in HIV-infected persons, using biomarker levels, could enable targeted interventions prior to the development of irreversible kidney damage. Additionally, these research objectives will lay foundation for future longitudinal investigations examining the utilities of biomarkers for the detection of drug toxicity, particulary among HIV-infected persons receiving nephrotoxic therapies.